Monocarboxylate Transporters (MCTs) are members of the solute carrier 16 (SLC16) gene family. In mammalian species there are 14 known MCT isoforms and only four (MCT-1, -2, -3, -4) have been demonstrated to perform proton-linked transport of monocarboxylates such as lactate, pyruvate, butyrate, and ketone bodies.
Malignant tumors contain aerobic and hypoxic regions and intratumoral hypoxia increases the risk of cancer advancement, and metastasis. Tumor hypoxia leads to treatment failure, relapse and patient mortality as these cells are generally resistant to standard chemo- and radiation therapy. In regions of hypoxia, cancer cells metabolize glucose into lactate, whereas nearby aerobic cancer cells take up this lactate via the mono-carboxylate transporter 1 (MCT1) for oxidative phosphorylation. MCT1 expression is elevated in an array of human tumors including brain, breast, head, neck, lung and colon.
Under hypoxic conditions, cancer cells upregulate glucose transporters and consume large quantities of glucose. Cancer cells also upregulate glycolytic enzymes and convert glucose into lactate, which is then effluxed out of the cell via MCT4. The nearby aerobic cancer cells take up this lactate via the MCT1 for energy generation through oxidative phosphorylation. Thus, the limited glucose available to the tumor is used most efficiently via a synergistic metabolic symbiosis. This utilization of lactate as an energy substitute for survival prevents the aerobic cells from consuming large quantities of glucose. Targeted inhibition of MCT4 will lead to lactic acidosis and consequent death of hypoxic cells, while MCT1 inhibition will cause aerobic cancer cells to consume glucose instead of lactate, thus resulting in further stress and death of hypoxic cancer cells.
The inhibition of MCT1 may also be useful for treating autoimmune diseases and preventing organ transplant rejection. The rate of short term graft survival has been improved by current immunosuppressants, however in the past two decades there has been no improvement in the abilities of agents to promote long term graft survival. Recently it has been demonstrated that agents which inhibit MCT1 have been shown to aid prolonged allograft survival, prevent chronic rejection, and induce tolerance in rat allograft models. In an immune response, a rapid division of T cells occurs, and these activated T cells use glycolysis as their means for energy production. Interestingly, the activated T cells use glycolysis even though the cells exist in an aerobic environment. As MCT1 plays a critical role in the aerobic glycolysis of the activated T cells by exporting lactate, inhibition of MCT1 leads to a buildup of lactate in the cell. This in turn decreases glycolytic flux effectively limiting the proliferation of new lymphocytes.
There is a current need for agents that are useful for treating or preventing cancer or that are useful for treating or preventing autoimmune diseases or that are useful for preventing transplant rejection. There is also a need for agents that are useful for diagnosing cancer or autoimmune diseases or for imaging cancerous cells or cells involved in an autoimmune response.